Nu-(beta-phenoxyisopropyl) ethanolamines



Patented July 13, 1954 T lTED STATE 1}? FFICE N fl-PHENOXYIS OPROPYL) ETHANOEAMINES of Pennsylvania N Drawing. Application October 18, 1949, Serial No. 122,119

6 Claims.

This invention relates to certain new chemical compounds, more particularly certain new amino alcohols and organic and inorganic salts thereof.

The new chemical compounds according to th'm invention have utility as intermediates for use in the preparation of new halogen containing amines which are physiologically active agents and, more particularly, have adrenolytic or sympathicolytic activity.

From the broad standpoint the new compounds according to this invention have the structure shown by the following formula:

in which:

A is a member of the group consisting of aryl and substituted aryl groups.

Y is a member of the group consisting of oxygen and sulfur.

Z is a member of the group consisting of alkyl, alkenyl, aralkyl, aralkyl substituted in the aryl portion, aryloxyalkyl, aryloxyalkyl substituted in the aryl portion, cyclohexylalkyl, thienylalkyl and thienyl alkyl substituted in the thienyl portion.

R is a member of the group consisting of alkyl groups.

R and R are members of the group consisting of hydrogen and alkyl groups containing not more than 6 carbon atoms.

n is an integer from 1 to 6.

More particularly, preferential compounds according to this invention will have the following structure:

in which:

A is a member or" the group consisting of aryl and substituted aryl groups in which the substitution is chosen from the group consisting of allryl groups containing not more than 4 carbon atoms, a hydroxy group, alkoxy groups containing not more than 4 carbon atoms, benzyloxy, chlorine, bromine, amino, acylamino containing not more than 4; carbon atoms, alkylamino containing not more than 4 carbon atoms, phenylamino and substituted phenylamino, cyclohexyl, phenyl, and aralkyl, the allryl part of which does not contain more than 2 carbon atoms.

Y is a member of the group consisting of oxygen and sulfur.

Z is a member of the group consisting of alkyl groups having not more than 8 carbon atoms; alkenyl groups having not more than 8 carbon atoms; aralkyl and substituted aralkyl groups; the alkylene portions of which do not contain more than 4 carbon atoms and the aryl substituents of which are members of the group consisting of alkoxy groups containing not more than 4 carbon atoms; hydroxy, chlorine, bromine, amino, acylamino, aikylamino and alkyl groups in which the number of carbon atoms does not exceed 4; aryloxyalkyl and substituted. aryloxyalkyl groups, the alkylene parts of which do not contain more than 3 carbon atoms and the aryl substituents of which are members of the group consisting of methyl, ethyl, hydroxy, alkoxy groups containing not more than carbon atoms, chlorine, bromine, amino, acylamino and alkylamino groups in which the number of carbon atoms does not exceed 4; cyclohexylalkyl groups in which the number of carbon atoms of the alkylene portion does not exceed 2; thienylalkyl groups in which the alkylene portion does not contain more than 3 carbon atoms; and thienylalkyl groups substituted in the thienyl portion by chlorine or bromine.

R is a member of the group consisting of alkyl groups having not more than 4 carbon atoms.

R and R" are members of the group consisting of hydrogen and alkyl groups such that the sum of the carbon atoms in R and R." does not exceed 6.

n is an integer from 1 to 6.

Still more particularly, compounds in accordance with this invention will have the following formula:

4 carbon atoms; hydroxy, chlorine, bromine,

amino, acylamino, alkylaminc and alkyl groups in which the number of carbon atoms does not exceed 4; aryloxyalkyl and substituted aryloxyalkyl groups, the alkylene parts of which do not contain more than 3 carbon atoms and the aryl substituents of which are members of the group consisting of methyl, ethyl, hydroxy, alkoxy groups containing not more than 4 carbon atoms, chlorine, bromine, amino, acylamino and alkylamino groups in which the number of carbon atoms does not exceed 4; cyclohexylalkyl groups in which the number of carbon atoms of the alkylene portion does not exceed 2; thienylalltyl groups in which the alkylene portiondoes not contain more than 3 carbon atoms; and thienylalkyl groups substituted in the thienyl portion by chlorine or bromine.

Where hereinafter the symbols A, Y, Z, R, R and R" and n are mentioned, they will indicate the substituents indicated for them in connection with the above general formula.

The organic and inorganic salts contemplated by this invention include by way of example salts or the bases formed with organic acids such,for example, as glycolie, oxalic, maleic, camphorsulionic, etc., and inorganic acids such as, for example, sulfamic, hydrochloric, hydrobromic, sulfuric, phosphoric, etc. More specifically, the inorganic and organic salts will be such as are prepared with inorganic and organic acids having an ionization constant not less than l lat 18 C.

The compounds in accordance with this invention and as identified by the above structural formula may be prepared variously by one of four general methods, from the following general description of which procedure for the preparation of all of the several compounds will be apparent to those skilled in the art.

The compounds used as starting materials for the synthesis of compounds of this invention are either known substances or, being made obvious, can be prepared by Well known methods.

METHOD A A halohydrin of the type R-CH-(CH2)"X or an alkylene oxide of the type RCH-CH2 is added to the sodium salt of a compound of the type AYI-I in refluxing alcohol to form an alcohol having the formula AY(CHz),.-C|)H-R This same alcohol may also be obtained by reducing the corresponding ketone with hydrogen in the presence or" a suitable hydrogenation catalyst, as, for example,"platinum, palladium, or activated nickel (reference: Hurd and Perletz: J. A. (3.8. 68,38 (1946).

The halide, formed by treating the alcohol with a suitable halogenating agent such as, for

example, thionyl chloride, thionyl bromide, etc.,

is added to an amino alcohol of the type HzNOH-CHOH When the resulting mixture is heated, the temperature employed depending upon the reactivity of the halide chosen, there is formed the N-substituted amino alcohol of the formula In this process it is advantageous to employ an excess of the primary amino alcohol.

The group Z is introduced into the molecule by heating together the secondary amino alcohol produced above with a halide Z-X. This may be carried out either in the presence of excess amino alcohol, or in the presence of an acid binding agent such as potassium carbonate. In most cases the reaction is conveniently carried out in a suitable solvent such as ethyl alcohol toluene, etc., but it may be carried out without such a solvent.

METHOD B The secondary amino alcohol produced as in Method A above may also be obtained by means or the following reaction:

This reduction may be carried out by dissolving equimolar quantities of lzetone and amine in a solvent as, for example, methyl alcohol, ethyl alcohol, cyclohexane, etc. The solution should be agitated under hydrogen pressure in the presence of a suitable hydrogenation catalyst such as platinum, palladium or activated nickel.

The amino alcohol so produced may be treated as in Method A above to introduce the radical Z.

METHOD C The ketones used as starting materials in Method B may also be used in the reaction which may be carried out in the same manner as described in Method B above. The secondary amine resulting ma then be reacted with alkylene halohydrin either in absence of a solvent, or in the presence of a solvent such as ethyl alcohol benzene, toluene or xylene. Unless one employs an excess of the amine, it will be advantageous to use an acid binding agent such as potassium carbonate, sodium bicarbonate, 01- magnesium oxide:

AY(CH2),.CHR XcH-oH-on ZNH R R AY o 1;)flo11ri ZN(|3H-CH-OH R! RI! If desired, the tertiary amino alcohol may also be formed by heating the secondary amin together with an allzylene oxide; rather than utilizing the alkylene halohydrin in the reaction.

METHOD D The secondary amine A-Y(CHz),.CHR

ZNH

prepared in Method 0 above may also be made by an alternative method. This involves treating a primary amine of the type A Y om JHR N Hz with an aldehyde or ketone and reducing the resulting mixture as described in Method B above. The tertiary amino alcohol is formed from the secondary amine by the use of either an alkylene halohydrin or an alkylene oxide as described in Method C.

In using the amino alcohols according to this invention as intermediates for the production of the corresponding halogen containing amines, the hydroxyl group of the amino alcohols is replaced with a halogen atom, as chlorine 01' bromine, which will be readily accomplished by reacting the amino alcohol with a halogenating agent, as thinoyl chloride or thionyl bromide, or the like. An excess of the halogenating agent may be employed as a solvent in this reaction, or a solvent such as chloroform, benzene or other solvent may be used.

The following examples will be illustrative of the various types of compounds and of specific compounds in accordance with the invention and procedure for their preparation and will, it is believed, serve to make fully apparent all of the compounds embraced by the general formula given above and the preparation thereof, respectively, it being noted that the utility indicated for the several compounds flows from the elements of the general structure common to all of them.

Example 1 N (phenoxyisopropyl) N benzylethanolamine:

@oomoH-om This compound will be prepared by Method A above as follows:

Step 1.-In a 500 ml. flask equipped with gas inlet tube, dropping funnel and reflux condenser is placed 139 g. of 1-phenoxy-2-propanol. A stream of dry air is bubbled through the alcohol while 55 g. of thionyl chloride is added dropwise with external cooling. The stream of dry air is continued for about six hours or until most of the hydrogen chloride has been expelled and then another 55 g. of thionyl chloride is added. The reaction mixture is allowed to stand twenty-four hours, a few drops of pyridine are added and the mixture heated four hours on the steam bath. The cooled reaction mixture is poured into water, the crude product is washed with dilute sodium bicarbonate solution and finally taken up in benzene. The benzene is distilled at ordinary pressure and the residue distilled in vacuo to yield 60-70% of l-phenoxy-2-chloropropane, B. P. 93-9 l C./5 mm.

Step 2.-To 494 g. of ethanolamine, heated to approximately 150 C. in a 500 ml. flask equipped with stirrer, condenser and dropping funnel, is added g. of l-phenoxy-Z-chloro-propane with mechanical stirring. The reaction mixture is then heated to reflux for three hours, cooled and poured into a liter of water. The organic layer is extracted into other and the ether solution is extracted with dilute hydrochloric acid. The aqueous acid solution is then made alkaline with 40% sodium hydroxide solution and the organic base is extracted into ether. Removal of the ether leaves N (phenoxyisopropyl) ethanolamine which, after recrystallization from hexane, melts at 70.572 C.

Step 3.To 43 g. of N-(phenoxyisopropyl) ethanolamine dissolved in 500 ml. of alcohol in a 1000 ml, flask equipped with stirrer and condenser is added 28 g. of benzyl chloride and 18.5 g. of sodium bicarbonate. The mixture is stirred and refluxed for ten hours and then approximately half the alcohol is removed by distilla tion. The remaining solution is poured into 500 ml. of water and the organic material extracted with three ml. portions of ether. The combined ether extracts are washed with water, dried over anhydrous potassium carbonate and filtered. After removal of the ether, the residue is distilled in vacuo to yield N-(phenoxyisopropyD- N-benzylethanolamine, B. P. 163-168 C./0.2 mm.

As exemplifying the use of this product as an intermediate, a solution of 20 g. of the above amino alcohol is dissolved in 50 ml. of dry chloroform and treated with dry hydrogen chloride until acid. Then a solution of 9 g. of thionyl chloride in 50 ml. of dry chloroform is added and the reaction mixture is heated by a Water bath at Bil-60 C. for two hours. Most of the chloroform is removed by distillotion under reduced pressure. Addition of ether to the residue causes the product to crystallize. After recrystallization from a mixture of alcohol and ether, the N- (phenoxyisopropyl) N benzyl-fl-chlorethylamine hydrochloride melts at 137.5440 C.

The free base of N phenoxyisopropyl N- benzyl-fi-chlorethylamine hydrochloride can be liberated in the following manner. Thirty-four grams of the hydrochloride is suspended in 20 ml. of water containing 4.0 g. of sodium hydroxide and the mixture is shaken with 100 ml. of benzene. After the solid disappears, the benzene layer is separated, dried over anhydrous sodium sulfate, filtered and the solvent distilled at reduced pressure. The free base which remains solidifies when chilled and is recrystallized from petroleum ether. The recrystallized N -phenoxyisopibopyl-N-benzyl 9 chlorethylamine melts at 38-4 C.

Example 2 N-(o-methylphenoxyisopropyl) N benzylethanolamine This compound will be prepared by Method A above as follows:

One mole of o-cresol and 300 ml. of alcohol are placed in a flask fitted with stirrer, reflux condenser and dropping funnel. A solution of 40 g. of sodium hydroxide in 40 ml. of water is added, the solution of sodium o-cresoate is heated to refluxing and one mole of propylene chlorohydrin is added with stirring over a two hour period. After the addition is complete, the reaction mixture is refluxed an additional five hours. Most of the alcohol is removed by distillation under diminished pressure, the residue is dissolved in benzene and washed several times with water and then with 10% sodium hydroxide solution. The benzene is then distilled and the residue is distilled in vacuo. l-(o-methyl-phenoxy) -2-pro- 7 panol distils at 86-88 C./2 mm. The p-nitrobene zoate ester melts at 95.5--96 C.

The end product is formed from 1-(omethylphenoxy) -2-propanol as in the manner described under Example 1 by halogenation with thionyl chloride to form 1(omethylphenoxy) -2-ohloropropane, B. P. 94-95 C./3 n1m., which, in turn, is reacted with ethanolamine to form the secondary amino alcohol l-(o-methylphenoxy) -2-propyl ethanolamine, M. P. 57.5-59" C. The benzyl group is introduced by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amino-alcohol where used as an intermediate is then treated with thionyl chloride to produce N- (o-methylphenoxyisopropyl) -N-benzyl-fs-chlorethylamine hydrochloride, which melts at 1535-1545 C.

Example 3 N- (m-methylphenoxyisopropyl) -N- benzylethanolamine In the preparation of this compound the procedure of Example 2 will be followed using as a starting material an equimolar amount of m-cresol in place of o-cresol. The m-cresol is converted with sodium hydroxide to the sodium salt, which is then refluxed with propylene chlorohydrin to obtain m-methylphenoxyisopropanol.

Halogenation of the m-methylphenoxyisopropanol with thionyl chloride, as in Example 1, forms m-methylphenoxyisopropyl chloride, B. P. 9S.5-98 C. at mm., which, in turn, is reacted with ethanolamine to form the secondary amino alcohol N-(m-methylphenoxyisopropyl) ethanolamine, M. P. 57-58 C. The benzyl group is introduced into the molecule by heating the secondary amino alcohol together with benzyl chloride. The resulting tertiary amino alcohol may be converted with thionyl chloride to N-( -mmethylphenoxyisopropyl) -N- benzyl-B-chlorethylamine hydrochloride, M. P. 133-134 C.

Example 4 N- (p-methylphenoxyisopropyl) N-benzylethanolamine A solution of 216 g. of p-cresol, 300 ml. of alcohol, 80 g. of sodium hydroxide and 85 ml. of water is heated to reflux While 188 g. of propylene chlorohydrin is added dropwise with stirring. The mixture is refluxed five hours, filtered and most of the alcohol removed under reduced pressure. The residue is dissolved in benzene, washed with sodium hydroxide solution and distilled to give 1-(p-methylphenoxy)-2-propanol boiling at fill-106 C./4 mm.

A stream of dry air is passed through 272 g. of cooled i-(p-methylphenoxy) -2-propanol while 143 g. of thionyl chloride is added dropwise. After three hours another 143 g. portion of thionyl chloride is added, followed by 3 ml. of dry pyridine. The reaction mixture is heated at YO-80 C. for 4 /2 hours, diluted with benzene, washed with sodiumbicarbonate solutionand distilled. The

8 1- (p-methyl-phenoxy) -2-chloropropane at 6-77" C. at 2 mm.

The chloro compound (225 g.) is introduced dropwise into 223 g. of refluxing ethanolamine. After three hours, the mixture is poured into water and the water-insoluble material is taken up in ether. The amino is extracted into dilute hydrochloric acid, the acid solution is made basic and extracted with ether. Distillation of the solvent leaves the solid N- (p-methyl-phenoxyisopropyl) ethanolainine, which melts at (SB- C. after recrystallization from hexane.

A mixture of g. of the above secondary amino alcohol, 60 g. of benzyl chloride, 25 g. of sodium carbonate and 500 ml. of alcohol is stirred and refluxed for nine hours. Half of the alcohol is distilled off and the concentrated mixture is refluxed an additional three hours. The product isolated by adding water, extracting the oil into ether and distilling. N-(p-methylphenoxyisopropyl)-N-benzy1ethanolamine is collected at l59-163 C./0.22 mm.

For the production of the corresponding chlorethylamine dry hydrogen chloride is passed into a solution of 69 g. of the tertiary amino alcohol and 200 ml. of chloroform. When the solution is acid, 30 g. of thionyl chloride is added and the solution refluxed for two hours. Removal of the solvent and recrystallization of the residue from alcohol and ether gives N-(p-methylphenoxyisopropyl) -Nbenzyl-fichlorethylamine hydrochloride which melts at l38-140 C.

Example 5 N-(o-ch1orophenoxyisopropyl) -N- benzylethanolamine distils The procedure of Example 4 will be followed in the preparation of this compound using an equimolar amount of o-chlorophenol to replace p-cresol as a starting material to form l-(ochlorophenoxy) 2 propanol which distils at 109-114 C. at 3 mm. and forms a p-nitrobenzoate ester which melts at 97-975 C.

The halogenation of the alcohol with thionyl chloride prepares the 1-(o-chlorophenoxy)-2- chloropropane, B. P. ill-114 C. per 5 mm, which is reacted with ethanolamine to form the secondary amino alcohol N-(o-chlorophenoxyisopropyl)-ethanolamine. The introduction of the N-benzyl group is accomplished by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amino alcohol may be treated with thionyl chloride to produce N- (0 chlorophenoxyisopropyl) N benzyl B- chlorethylamine hydrochloride.

Example 6 N (p chlorophenoxyisopropyl) N benzyleth anolamine In this preparation the procedure of Example 4 will be followed using p-chlorophenol as a starting material. The p-chloropnenol is converted with sodium hydroxide to the sodium salt which is refluxed with propylene chlorohydrin to obtain the p-chlorophenoxyisopropanol, which distils at 125-l30 C. at 6 mm. and forms a pnitrobenzoate ester, M. P. 76.5-'77 C.

The end product is prepared as described in Example l by halogenation of the p-chlorophenoxyisopropanol with thionyl chloride to form p-chlorophenoxyisopropyl chloride, B. P. 84=-90 C. at 2 mm; M. P. 37-39 0., which, in turn, is reacted with ethanolamine to form the secondary amino alcohol N-(p-chlorophenoxyisopropyl) ethanolamine. The N-benzyl group is introduced by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amino alcohol may be treated with thionyl chloride to produce N-(p-chlorophenoxyisopropyl) -N-benzyl-fi-chlorethylamine hydrochloride, M. P. 158.5-159 C.

Ercample 7 N (p methoxyphenoxyisopropyl) N benzylethanolamine:

(redo-Q CHz-ClE-CHa A solution of 372 g. of p-methoxyphenol, 500 ml. of alcohol, 120 g. of sodium hydroxide and 140 ml. of water is heated to reflux while 282 g. of propylene chlorohydrin is added with stirring over a two hour period. The mixture is refluxed for three hours, cooled and filtered to remove sodium chloride. Most of the alcohol is distilled at reduced pressure and the residue is dissolved in 600 ml. of benzene. The benzene solution is extracted with sodium hydroxide solution, then with water and the solvent is evaporated. The solid residue is D-methoxyphenoxyisopropanol, which melts at 63-64" C. after recrystallization from benzene-petroleum ether.

A slow stream of dry air is passed into a solution of 300 g. of p-methoxyphenoxyisopropanol and 1500 ml. of dry benzene while 146 g. of thionyl chloride is added dropwise with cooling. After six hours another 146 g. portion of thionyl chloride is added and the solution allowed to stand overnight. Three cc. of dry pyridine is then added and the solution refluxed for six hours. The cooled benzene solution is poured into water and washed repeatedly with sodium bicarbonate solution. Distillation of the solvent followed by distillation of the residue in vacuo yields p-methoxyphenoxyisopropyl chloride, B. P.

90-95 C./1 mm.

The 1- (p-methoxyphenoxy) -2-chloropropane is reacted with ethanolamine to form the secondary amino alcohol N-(p-methoxyphenoxyisopropyl) ethanolamine, M. P. 5355 C. The N-benzyl group is introduced by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amino alcohol may be treated with thionyl chloride to produce N-(p-methoxyphenoxyisopropyl) -N-benzyl-B-chlorethylamine hydrochloride, which melts at 152-153" 0.

Example 8 N (p phenylphenoxyisopropyl) N benzylethanolamine:

Dry air is bubbled through a mixture of 455 of l-(p-phenylphenoxy) -2-propanol and a liter of dry chloroform while one mole of thionyl chloride is added dropwise over a period of four hours. Twenty-four hours later another mole of thionyl chloride is added and the mixture allowed to stand several hours. Two ml. of dry pyridine is added and the mixture refluxed for six hours. Removal of the solvent under reduced pressure leaves l-(p-phenylphenoxy)-2-chloropropane, which melts at 75-76 C. after recrystallization from alcohol.

The l-(p-phenylphenoxy) -2-chloropropane is added portionwise to refluxing ethanolamine to form the secondary amino alcohol N-(p-phenylphenoxyisopropyl) ethanolamine. The introduction of the N-benzyl group is accomplished by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amino alcohol may be treated with thionyl chloride to produce N (p phenylphenoxyisopropyl) N benzylc-chlorethylamine hydrochloride.

Example 9 N (p acetylaminophenoxyisopropyl) N- benzylethanolamine:

O H enhance-Q0 CH2CECH:

This compound is prepared using the procedure of Method B in which a. solution of 138 g. of chloroacetone and 3 g. of potassium iodide in cc. of acetone is added dropwise to a starting mixture of g. of p-acetylaminophenol. 14.6 g. of potassium carbonate, and 200 cc. of acetone. The mixture is stirred and refluxed for 5 hours followed by stirring for 18 hours at room temperature. The reaction mixture is filtered, the solid washed with acetone and recrystallized from water and alcohol successively. The resulting p-acetylaminophenoxyacetone' melts at 160.5-l63 C.

10 g. of the ketone are shaken together with 2.9 g. of ethanolamine and 200 cc. alcohol under a hydrogen pressure of 50 p. s. i. at 75 C. in the presence of platinum catalyst. Upon completion of the hydrogenation the catalyst is removed by filtration and the solvent distilled off under reduced pressure. The N-(pacety1aminophenoxyisopropyD-ethanolamine forms a hydrochloride which melts at 172 C.

The secondary amine formed above is benzylated with benzyl chloride in alcohol solution in the presence of potassium carbonate. The resulting tertiary amino alcohol may be treated with thionyl chloride to produce N-(acetylaminophenoxyisopropyl)N-benzyl-,6-ch1orethylamine hydrochloride.

Example 10 @oom-oreom The procedure of Example 4 will be followed in the preparation of this compound using an equimolar amount of o-tert.-butylphenol to replace p-eresol as a starting material. In the first step 1 tert. butylphenoxy)-2-propanol is formed.

The halogenation of the secondary alcohol with thionyl chloride prepares the 1-(o-tert.-butylphenoxy) -2-chloropropane which is reacted with ethanolamine to form the secondary amino alcohol N-(o-tert.-butylphenoxyisopropyl) ethanolamine. The introduction of the N-benzyl group is accomplished by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amino alcohol may be treated with thionyl chloride to produce N-(o-tert-butylphenoxyisopropyl)-N-benzyl-,B-chlorethylamine hydrochloride.

Example 11 N-(phenoxyisopropyl) N (o-methylbenzyl) ethanolamine:

Q GH2 N- (phenoxyisopropyl) -ethanolamine, an intermediate in the synthesis of Example 1, is employed as starting material. The amino alcohol is reacted with o-methylbenzyl chloride in alcohol solution in the presence of sodium bicarbonate in the same manner as described under Example 1 for benzyl chloride. This product, on reaction with thionyl chloride, in chloroform solution as described above will produce N-(phenoxyisopropyl) N (o methylbenzyl) 8 chlorethylamine hydrochloride.

Example 12 N (phenoxyisopropyl) -N- (p-methoxybenzyl) ethanolamine:

N- (phenoxyisopropyl) -ethanolamine, an inter mediate in the synthesis of Example 1, is employed as starting material. A solution of 39 g. of N(phenoxyisopropyl)-ethanolamine, 16 g. of p nethoxybenzyl chloride and 100 ml. of dry benzene is refluxed for six hours. One hundred m1. of water is added and the layers separated. After removal of the benzene, the residue is distilled to yield a small amount of starting amino alcohol and 22 g. of N-phenoxyisopropyl-N-(p-methoxybenzyD-ethanolamine, B. P. 142-157 C. at 0.2

Using the above tertiary amino alcohol as an intermediate, 21 grams thereof is dissolved in 100 m1. of chloroform and dry hydrogen chloride is introduced until the solution is acid. Ten grams of thionyl chloride in 25 ml. of chloroform is added, the solution is warmed to 35 C. for one half hour and then refluxed for an hour. Removal of the solvent in vacuo leaves an oil which solidifies on addition of ether. The solid, N- (phenoxyisopropyl) N (p-methoxybenzyl) 43- chlorethylamine hydrochloride, is collected and recrystallized from alcohol and ether, M- P. 146.5-14'7.5 C.

Example 13 N- (phenoxyisopropyl) -N- (3,4-dichlorobenzyl) ethanolamine Q-oom-on-om N (phenoxyisopropyl) ethanolamine, an intermediate in the synthesis of Example 1, is employed as starting material. The amino alcohol is reacted with 3,4-di-chlorobenzyl chloride in alcohol solution in the presence of sodium bicarbonate in the same manner as described under Example 1 for benzyl chloride. Reaction of this product with thionyl chloride, in chloroform solution as described above Will produce N- (phenoxyisopropyl) N-(3,l-dichlorobenzyl) B chlorethylamine hydrochloride which melts at -146 C.

Example 14 N (phenoxyisopropyl) N (3,4 dimethoxybenzyl) -ethanolamine:

| CHaO N-(phenoxyisopropyl) -N-ethanolamine, an intermediate in the synthesis of Example 1, is employed as starting material.

A solution of 48 g. of N-(phenoxyisopropyD- ethanolamine, 28 g. of 3,4-dimethoxybenzyl bromide and ml. of toluene is heated gradually from room temperature to 110 C. over a period of 1 hours and held at that temperature for an hour. The cooled reaction mixture is extracted with water and the organic layer distilled. After removal of the solvent, the residue is distilled in vacuo, yielding N-phenoxyisopropyl N (3, l-dimethoxybenzyl) -ethanolamine which distils at l88-189 C. at 0.08 mm. Reaction of this product with thionyl chloride, in chloroform solution as described above will produce N-(phenoxyisopropyl) N- (3,4-dimethoxybenzyl) -chlorethylamine hydrochloride, M. P. 128.5-129.5 C.

Example 15 N (o-methylphenoxyisopropyl) -N-(o-methylbenzyl) -ethano1amine:

N (o methylphenoxyisopropyl) ethanolamine, an intermediate in the synthesis of Example 2, is employed as a starting material. The amino alcohol is reacted with o-methylbenzyl chloride in alcohol solution in the presence of sodium bicarbonate in the same manner as described under Example 1 for benzyl chloride. Reaction of this product with thionyl chloride in chloroform solution as described above will produce N- (phenoxyisopropyl) -N- (o-methylbenzyl) p-chlorethylamine hydrochloride.

13 Example 16 N (2 methoxy 4 allylphenoxyisopropyD- N (Z-dichlorobenzyl) -ethanolamine:

OCH:

Cl-QOQ:

treated with thionyl chloride to produce N-(2- methoxy 4 allylphenoxyisopropyl) N (2,4- dichlorobenzyl) c chlorethylamine hydrochloride.

Example 17 N (phenoxyisopropyl) N (phenoxyethybethanolamine:

Q-oom-cm N phenoxyisopropyl) -ethanolamine, an intermediate in the synthesis of Example 1, is employed as starting material.

A mixture of 48 g. of N-(phenoxyisopropyl)- ethanolamine and 25 g. of phenoxyethyl bromide is heated at 120 C. for three hours and then heated gradually to 145 C. over a four hour period. The cooled mixture is dissolved in 100 ml. of benzene and extracted thrice with water. Distillation of the benzene layer yields N-phenoxyisopropyl-N- (phenoxyethyl) -ethanolamine which distils at ISO-167 C. at 0.2 mm.

For production of the corresponding chlorethylamine, dry hydrogen chloride is introduced into a solution of 29 g. of the above amino alcohol in 100 ml. of dry chloroform until the solution is acid. The acidified solution is cooled while 13.4 g. of thionyl chloride is added and, after the addition is complete, heated to reflux for 1 hours. Removal of the solvent and recrystallization of the residue from alcohol and ether gives phenoxyisopropyl N phenoxyethyl B- chlorethylamine hydrochloride which melts at Eatample 18 N,N-bis- (phenoxyisopropyl) -ethanolamine:

This compound will be prepared by the procedure of Method D as described above. 25 g. of phenoxyisopropylamine and 25 g. of phenoxyacetone are mixed and heated at 110 C. for 2 hours. Water formed in the reaction is removed by heating the mixture under vacuum at -125 after one-half hour. Alcohol is added to the cooled mixture and the solution is shaken under 3 atmospheres of hydrogen pressure in the presence of platinum catalyst. After removal of the catalyst and solvent the residue is distilled to yield bis-(phenoxyisopropyl)-amine, B. P. 151- 153 C. at 0.3 mm.

A mixture of 28.5 g. of the above secondary amine, 1.8 g. of water and 8.8 g. of ethylene oxide is heated at 100 C. for 9 hours in a sealed vessel followed by heating at C. for 4 hours. The cooled reaction mixture is dissolved in ether, dried over potassium carbonate, filtered and distilled. The product N,N-bis-(phenoxyisopropyl)ethanolamine boils at 183-190 C. at 0.2 mm. and forms a picrate which melts at Mil-142 C.

Example 19 N (a naphthoxyisopropyl) N benzylethanolamine The procedure of Example 7 will be followed, employing a-naphthol as starting material in place of p methoxyphenol. The 1-( cc naphthoxy)-2-propanol is recrystallized from hexane and melts at 66-68 C. Halogenation of the secondary alcohol with thionyl chloride prepares the l-naphthoxy-Z-isopropyl chloride, B. P. 117120 C./0.22 mm., which is reacted with ethanolamine to form the secondary amino alcohol, M. P. 7077.5 C. The resulting amino alcohol is reacted with benzyl chloride in the same manner as described under Example 1 in the presence of sodium bicarbonate. The product on reaction with thionyl chloride in chloroform solution will be converted to N-(a-naphthoxyisopropyl)-N- benzyl-c-chlorethylamine hydrochloride, M. P. I'M-179 C.

Example 20 N (p isopropylphenoxyisopropyl N (omethylphenoxyethyl) -ethanolamine:

In this preparation the procedure of Example 4 will be followed using as a starting material pisopropylphenol in place of p-cresol. The phenol is converted by means of sodium hydroxide to the sodium salt which is refluxed with propylene chlorohydrin to obtain p-isopropylphenoxy iso propanol.

The product N -(p-isopropylphenoxyisopropyl) ethanolamine is formed in the same manner as described in Example 4 by halogenation of the p-isopropylphenoxyisopropanol with thionyl chloride to form p-iscpropylphenoxy isopropyl chloride which is reacted with ethanolamine to form the secondary amino alcohol. The secondary amino alcohol will be reacted with o-methyl- Example 21 N (1 7 phenoxy 3 butyl) N benzylcthanolamine:

In this preparation the procedure of Example 2 will be followed using as a starting material L an equal amount of phenol. The phenol is converted to the sodium salt with sodium hydroxide, which salt is then refluxed with 1-bromo-3- butanol which is employed in place of propylene chlorohydrin.

The l-phenoxy-3-butanolris converted to the chloride by halogenation with thionyl chloride. The chloride is then reacted with ethanolamine to form the secondary amino alcohol N-(lphenoxy-B-butyl)-ethanolamine. The N-benzyl group is introduced as in the same manner as in Example 2, by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amino alcohol as an intermediate on treatment with thionyl chloride will be converted to N (l phenoxy 3 butyl) I benzyl- ,e-chlorethyl amine hydrochloride.

Example 22 N (phenoxyisopropyl) N ethylethanolamine:

N- (phenoxyinsopropyl) -ethanolamine is formed as an intermediate in the procedure of Example 1. This compound is reacted with ethyl iodide place of benz-yl chloride in the presence of sodium bicarbonate as described in Example 1. The resulting tertiary amino alcohol may be treated with thionyl chloride to produce N- phenoxyisopropyl) N ethyl {i chlorethylamine hydrochloride.

Example 23 N- (phenoxyisopropyl) -N-allylethanolamine:

Example 24 N -(phenoxyisopropyl) N cyclohexylmethylethanolamine:

N-(phenoxyisopropyl) -ethanolamine is formed as an intermediate in the procedure of Example l. This compound is reacted with cyclohc yimethyl bromide in place of benzyl chloride in the presence of sodium bicarbonate as described in Example 1. The resulting tertiary amino alcohol may be treated with thionyl chloride to produce N (phenoxyisopropyl) N cyclohexylmethyl-c-chlorethylamine hydrochloride.

Example 25 N (thiophenoxyisopropyl) N benzylethanolamine:

In this preparation the procedure of Example 4 will be followed using as a starting material an equimolar amount of thiophenol in place of pcresol. The sodium salt of the thiophonol, which is prepared with sodium hydroxide is refluxed together with propylene chlorhydrin to obtain thiophenoxyisopropanol.

The end product is formed in the manner described under Example 4 by halogenation of the thiophenoxyisopropanol with thionyl chloride to form the halide of the compound which, in turn, is reacted with ethanolamine to form the secondary amino alcohol. The N-benzyl group is then introduced as described in Example 2 by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amine alcohol may be reacted with thionyl chloride to produce N (thiophenoxyisopropyl) N henzyle-ehlorethylamine hydrochloride.

Example 26 N (phenoxyisopropyl) N benzyl l amino- Z-propanol:

In the preparation of this compound the 1- phenoxyisopropyl-Z chloropropane is reacted with isoprcpanolamine instead of ethanolaminc under the conditions described in Example 1. The resulting secondary amino alcohol, M. P. 69-71 C. is treated with benzyl chloride to prepare the N-benzyl derivative, which distils at 149-1515" C./0.2 mm. The resulting tertiary amino alcohol may be converted to the halide by treatment with thionyl chloride to produce N-(phenoxyisopropyl N benzyl 1 amino 2 chloropropane hydrochloride, M. P. lad-147 C.

Example 27 N (phenoxyisopropyl) N benzyl 2 amino- 1 -propanol:

Example 28 N-(phenoxyisopropyl) -N benzyl 2 amino- 3-butan01:

I Ooom-og-om N-CH-CH-OH Phenoxyisopropyl chloride, formed as an intermediate in the process described in Example 1, is reacted with 2-amino-3-butanol instead of ethanolamine in the same manner as described in Example 1. The secondary amino alcohol so produced is similarly reacted with benzyl chloride in the presence of sodium bicarbonate to form the tertiary amino alcohol which is then treated with tliinoyl chloride to produce N- (phenoxyisopropyl) N benzyl 2 amino 3- chlorobutane hydrochloride.

Example 29 N-(l-phenoxy-Z-butyl) N benzylethanolamine:

( o cakes-011F011:

NCH2C'H2OH CH2 The procedure of Example 1 will be followed in the preparation of this compound, replacing the l-phenoxy-Z-propanol with an equimolar amount of l-phenoxy-Z-butanol as a starting material. The halide of this alcohol which is formed by reaction with thionyl chloride is reacted iWth ethanolamine to form the secondary amino alcohol N-(l-phenoxy-Z-butyl) -ethanolamine. The introduction of the N-benzyl group is accomplished as described in Example 1 in the presence of sodium bicarbonate. This tertiary amino alcohol may be converted to the halide by reaction with thionyl chloride to form N-(1-phenoxy-2 butyl) N benzyl [3 chlorethylamine hydrochloride.

Example 30 N-(p-tert. butylphenoxyisopropyl) N benzylethanolamine The procedure of Example 1 will be followed in preparation of this compound, replacing the 1-phenoxy-2-propanol with an equimolar amount of 1-(p-tertiary butyl phenoxy)-2- propanol as a starting material. The halide of this aclohol which is formed by reaction with thionyl chloride is reacted with ethanolamine to form the secondary amino alcohol N-(ptertiarybutyl phenoxyisopropyl) N ethanolamine. The introduction of the N-benzyl group is accomplished as described in Example 1 in the presence of sodium bicarbonate. This amino alcohol may be converted to the halide by reaction with thionyl chloride to form N-(ptert.- butylphenoxyisopropyD-N benzyl ,9 chlorethylamine hydrochloride.

Example 31 N-(o-sec. butylphenoxyisopropyl) N benzylethanolamine:

The procedure of Example 1 will be followed in the preparation of this compound, replacing the l-phenoxy-Z-propanol with an equimolar amount of 1-(o-sec.-butyl phenoxy)-2-propanol as a starting material. The halide, B. P. 118-124 0/4. mm, of this alcohol, which is formed by reaction with thionyl chloride, is reacted with ethanolamine to form the secondary amino alcohol -1(osec. butyl phenoxy) -2propyl ethanolamine, M. P. 69.5-71.5 C. The introduction of the N-benzyl group is accomplished as described in Example 1 in the presence of sodium bicarbonate. The resulting tertiary amino alcohol, which distils at 162-172". C. at 0.35 mm. may be converted to the halide by reaction with thionyl chloride to form N-(o-secbutylphe'noxyisopropyD-N-benzyl-c chlorethylamine hydrochloride, M. P. 142-144" C.

Example 32 In this preparation the procedure of Example 2 will be followed using as a, starting material an equimolar amount of m-aminophenol in place of o-cresol. The sodium salt of the m-aminophenol which is prepared with sodium hydroxide is refluxed together with propylene chlorohydrin to obtain m-aminophenoxy-isopropanol.

The end product is formed in the manner described under Example 1 by halogenation of the m-aminophenoxyisopropanol with thionyl chlo-' ride to form the halide of the compound which, in turn, is reacted with ethanolamine to form the secondary amino alcohol. The N-benzyl group is then introduced as described in Example 2 by heating the secondary amino-alcohol with benzyl chloride. This tertiary amino alcohol may be reacted with thionyl chloride to produce N-(m-aminophenoxyisopropyl) N benzyl 8- chlorethylamine dihydrochloride.

In this preparation the procedure of Example 4 will be followed using as a starting material an equimolar amount of p-dimethylaminophenol in place of p-cresol. The sodium salt of the pdimethylaminophenol which is prepared with sodium hydroxide is refluxed together with propylene chlorohydrin to obtain p-dimethylaminophenoxyisopropanol.

- The end product is formed in the manner described under Example 1 by halogenation of the p-dimethylaminophenoxyisopropanol with thionyl chloride to form the halide or" the compound which, in turn, is reacted with ethanolamine to form the secondary amine alcohol. The N -benzyl group is then introduced as described in Example 2 by heating the secondary amino alcohol with benzyl chloride. This tertiary amino alcohol may be reacted with thionyl chloride to produce N-(pdimethylaminophenoxyisopropyl) N benzylc-chloroethylamine dihydrochloride.

Example 34 N (p phenylaminophenoxyisopropyl) N- benzylethanolamine:

In this preparation the procedure of Example 4 will be followed using as a starting material an equimolar amount of p-phenylaminophenol in place of p-cresol. The sodium salt of the p-phenylaminophenol which is prepared with sodium hydroxide is refluxed together with propylene chlorohydrin to obtain p-phenylaminophenoxyisopropanol.

The end product is formed in the manner described under Example 4 by halogenation of the p-phenylaminophenoxyisopropanol with thionyl chloride to form the halide of the compound which, in turn, is reacted with ethanolamine to form the secondary amino alcohol. The N-benzyl group is then introduced as described in Example 4 by heating the secondary amino alcohol with benzyl chloride. This tertiary amino alcohol may be reacted with thionyl chloride to produce N-(pphenylaminophenoxyisopropyl) N benzyl ,8- chloroethylamine hydrochloride.

Example 35 N (p cyclohexylphenoxyisopropyl) N- benzylethanolamine CHz-CH:

The procedure of Example 8 will be followed in the preparation of this compound, replacing the l-(p-phenylphenoxy)-2-propanol with an equiinolar amount of l-(p-cyclohexylphenoxy)-2- propanol as a starting material. The halide of this alcohol which is formed by reaction with thionyl chloride is reacted with ethanolamine to form the secondary amino alcohol N-(p-cyclohexylphenoxyisopropyl) -ethanolamine. The introduction of the N-benzyl group is accomplished as described in Example 1 in the presence of sodium bicarbonate. This tertiary amino alcohol may be converted to the halide by reaction with thionyl chloride to form N-(p-cyclohexylphenoxyisopropyl) N benzyl e chlorethylamine hydrochloride, M. P. l89.5-l90.5 C.

Example 36 N (p benzyloxyphenoxyisopropyl) N benzylethanolamine hydrochloride:

-omo-o CHz-CH-CHa l-(p-benzyloxyphenoxy)-2-propanol is prepared from hydroquinone monobenzyl ether and propylene chlorohydrin in the manner described in previous examples. The crude product separates from reaction mixture on cooling and is redissolved by addition of more alcohol. The l-(p-benzyloxyphenoxy)-2-propanol, M. P. 104- 105 C. is purified by recrystallization from benzene.

A chloroform solution of l-(p-benzyloxyphenoxy) -2-propanol is treated with thinoyl chloride as described for Example 4. The chloro compound is recrystallized from alcohol and melts at 67-69" C.

One hundred grams of l-(p-benzyloxyphenoxy) -2-chloropropane is added portionwise to 66 g. of boiling ethanolamine. After three hours, the mixture is poured into water, the solid collected and recrystallized from benzene, M. P. 12l-122 C.

Fifty-five grams of N-(p-benzyloxyphenoxyisopropyl) -ethanolamine is benzylated with 23 g. of benzyl chloride as described in Example 4. Dry hydrogen chloride is passed into an ether solution oi the crude product to form the hydrochloride salt which melts at 109.51l2 C. after recrystallization from acetone.

The N- (p-benzyloxyphenoxyisopropyl) -N-benzylethanolamine may be treated with thionyl chloride in chloroform solution as described in previous examples to form the [i-chlorethylamine hydrochloride, M. P. l52-154 C.

Example 37 N (p benzylphenoxyisopropyl) N benzylethanolamine:

In this preparation the procedure of Example 4 will be followed using as a starting material an equimolar amount of p-benzylphenol in place of p-cresol. The sodium salt of the p-benzylphenol which is prepared with sodium hydroxide is refluxed together with propylene chlorohydrin to obtain p-benzylphenoxyisopropanol. V

The end product is formed in the manner described under Example 4 by halogenation of the p-benzylphenoxyisopropanol in benzene solution with thionyl chloride to form the halide of the compound which, in turn, is reacted with ethanolamine to form the secondary amino alcohol. The N-benzyl group is then introduced as described Example 38 N-(o-bromophenoxyisopropyl) N benzylethanolamine:

In this preparation the procedure of Example 4 Will be followed using as a starting material an equimolar amount of o-bromophenol in place of p-cresol. The sodium salt of the o-bromophenol which is prepared with sodium hydroxide is refluxed together with propylene chlorohydrin to obtain o-brcmophenoxyisopropanol.

The end product is formed in the manner described under Example 4 by halogenation of the -bromophenoxyisopropanol with thionyl chloride to form the halide of the compound which, in turn, is reacted with ethanolamine to form the secondary amino alcohol. The N-benzyl group is then introduced as described in Example 4 by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amino alcohol may be reacted with thionyl chloride to produce N (o brornophenoxyisopropyl) l benzyl ,3- chloroethylamine hydrochloride.

Eavample 39 N -(phenoxyisopropyl) -N (p amino benzyl) ethanolamine:

N- (phenoxyisopropyl) -ethanolamine is formed as an intermediate in the procedure as outlined in Example 1. This compound is reacted with pnitrobenzyl chloride in the same manner as described for the similar reaction with benzyl chloride. The nitro group of the resulting tertiary amino alcohol is then reduced under hydrogen pressure in the presence of palladium or other suitable hydrogenation catalyst to N-(phenoxyisopropyl) N-(p aminobenzyl) ethanolamine. This compound may be treated with thionyl chloride to produce N (phenoxyisopropyl) N (paminobenzyl) -fl chlcroethylamine dihydrochloride Example 40 N (phenoxyisopropyl) N (p dimethylaminobenzyl) -ethanolamine:

A solution of phenoxyacetone and p-dimethylamino benzylamine in alcohol solution is agitated with hydrogen at approximately 8 atmospheres pressure and 70 C. in the presence of platinum oxide catalyst. The N-(phenoxyisopropyl) -p-dimethylaminobenzylamine is recovered by distillation and reacted with ethylene oxide under 22 pressure at -120" C. The N-(phenoxyisopropyl) -N- (p dimethylaminobenzyl) -ethanolamine so produced may be conv rted to the corresponding chloramine hydrochloride with thionyl chloride by the method employed in Example 1.

Example 41 N (phenoxyisopropyl) N (0 acetylamino benzyl) -ethanolamine:

N (phenoxyisop-ropyl) N ethanolamine is formed as an intermediate in the procedure of Example 1. This compound is reacted with o acetylaminobenzylchloide in place or" benzyl chloride in the presence of sodium bicarbonate as described in Example 1. The product may be treated with thionyl chloride to produce N-(phenoxyisopropyl) N (o acetylaminobenzyl) -5- chlorethylamine hydrochloride.

Example 42 N (phenoxyisopropyl) N (m hydroxyphenoxyethyl) -ethanolamine:

N -phenoxyisopropyl) ethanolamine is formed as an intermediate in the procedure of Example 1. An excess or this compound is reacted with m-hydroxyphenoxyethyl bromide in place of phenoxyethyl bromide as described in Example 17. The product amino alcohol be treated with thionyl chloride to produce N-(phenoxyisopropyl) N (m-hydroxyphenoxyethyl) e chlorethylamine hydrochloride.

Eat-ample 43 N phenoxyisopropyl) -N- (o-methoxyphenoxyethyl) -ethanolamine:

N phenoxyisopropyl) -ethanolamine is formed as an intermediate in the procedure of Example 1. This compound is reacted with o-rnethoxyphenoxyethyl bromide in place of phenoxyethyl bromide as described in Example 17. This amino alcohol may be treated with thionyl chlo ride to produce N-(phenoxyisopropyl) -N-(omethoxyphenoxyethyl) ,8 chlorethylamine hydrochloride.

Example 44 N (phenoxyisopropyl) N (p-chlorophenoxyethyl) -ethanolamine:

-OCH2CH-CH3 NCH2CH2OH N-(phenoxyisopropyl) -ethano1amine is formed Example N -(phenoxyisopropyl) N -(o-bromophenoxyethyl) -ethanolamine:

N-(phenoxyisopropyl) -ethanolamine is formed as an intermediate in the procedure of Example 1. This compound is reacted with o-bromophenoxyethyl bromide in place of phenoxyethyl bromide as described in Example 17. This amino alcohol is treated with thionyl chloride to produce N- (phenoxyisopropyl) -N-(o-bromophenoxyethyl) -,B-ch1orethylamine hydrochloride.

Example 46 N -(phenoxyisopropyl) N -(p-aminophenoxyethyl) -ethano1amine:

N -(p-acetylaminophenoxyisopropyl) N benzylethanolamine, an intermediate in the preparation of Example 48, is heated with 6 N-hydrochloric acid for 6 hours to remove the acetyl group. The N -(p-aminophenoxyisopropyl) -N- benzylethanolamine may be treated with thionyl chloride to produce the fl-chlorethylamine.

Example 47 N- (phenoxyisopropyl) N (p-acetylaminophenoxyethyl) -ethanolamine:

N-(phenoxyisopropyl) -ethanolamine is formed as an intermediate in the procedure of Example 1. This compound is reacted with p-acetylaminophenoxyethyl bromide in place of phenoxyethyl bromide as described in Example 17. This amino alcohol may be treated with thionyl chloride to produce N-(phenoxyisopropyl) -N-(pacetylaminophenoxyethyl)- p chlorethylamine hydrochloride.

Example 48 N -(phenoxyisopropyl) N -(p-dimethylaminophenoxyethyl) -ethanolamine:

N- (phenoxyisopropyl) -ethanolamine is formed as an intermediate in the procedure of Example 1. This compound is reacted with p-dimethylaminophenoxyethyl bromide in place of phenoxyethyl bromide as described in Example 17. The p-dimethylaminophenoxyethyl bromide will 24 be prepared from the sodium salt of p-dimethylaminophenol and ethylene dibromide in alcohol solution by the method employed by Hinsberg (Ann. 305, 283) to prepare p-acetylaminophenoxyethyl bromide. This amino alcohol, N-phenoxyisop-ropyl-N -(p-dimethylaminophenoxyethyl) ethanolamine, may be treated with thionyl chloride to produce N-(phenoxyisopropyD-N- (p-dimethylaminophenoxyethyl)-;8 chlorethylamine hydrochloride.

Example 49 N-(phenoxyisopropyl) N -(p chlorobenzyl)- ethanolamine N-(phenoxyisopropyl) -ethano1amine is heated in alcohol solution with p-chlorobenzyl chloride in the presence of sodium bicarbonate as described in the third step of Example 1. The product of the reaction, N-(phenoxyisopropyD- N-(p-chlorobenzyl) -ethanolamine, distils at C. at 0.3 mm.

This amino alcohol may be treated with thionyl chloride in chloroform solution in the same manner as described for Example 1 to form N- phenoxyisopropyl) N -(p chlorobenzyl) c chlorethylamine hydrochloride which melts at 143-444 C.

Example 50 N-(m-methoxyphenoxyisopropyl) N benzylethanolamine:

In this preparation the procedure of Example 4 is followed using as a starting material an equimolar amount of resorcinol monomethyl ether in place of p-cresol. The 1-(m-methoxyphenoxy)- Z-propanol so formed distils at 107-110 C../l mm. and is converted into l-(m-methoxyphenoxy) -2- chloropropane by reaction with thionyl chloride as described under Example 4. Alkylation of ethanolamine by the chloro compound produces N (m methoxyphenoxyisopropyl) ethanolamine which is benzylated with benzyl chloride in alcohol solution in the presence of sodium carbonate. This amino alcohol may be heated with thionyl chloride in chloroform solution to produce the B-chlorethylamine hydrochloride.

Example 51 N (3,4 dimethylphenoxyisopropyl) N benzylethanolamine This compound is prepared in the same manner as Example 4 with the substitution, in the first step, of 3,4-dimethylphenol for p-cresol. It melts at 63.566 C.

Example 52 N (2 ispropyl methylphenoxyisopropyl) -N-benzylethanolamine:

OH3CHOH3 o our-0341113 In the procedure of Example l, thymol replaces p-cresol as a starting material. When the sodium salt of thymol is heated in alcohol solution with propylene chlorohydrin, lJZ-isopropyl- 5-methylphenoxy) -2-propanol is formed. This is halogenated by means of thionyl chloride to produce 1-(2-isopropyl 5-methylphenoxy) -2-chloropropane which is employed to alkylate ethanolamine. The secondary amine is benzylated as described above. The hydroxy group may be replaced by chlorine as described in Example 4 to yield the chlorethylamine.

Example 53 N (o isopropylphenoxyisopropyl) N benzylethanclamine:

Example 54 N (in diethylaminophenoxyisopropyl) N benzylethanolamine The procedure of Example 34 will be followed with the p-din1ethylaminophenol replaced by an equivalent amount of m-diethylaminophenol.

Example 55 N (p sec. butylphenoxyisopropyl) N benzylethanolamine This compound is prepared in the same manner as Example 1, using l-(p-sec.-butylphenoxy) 2-propanol in place of l-phenoxy-Z-propanol.

26 Reaction of the alcohol with thionyl chloride forms l-(p-sec.-butylphenoxy) -2-chloropropane which is employed to alkylate ethanolamine. Benzylation with benzyl chloride as described in Example 1 yields the N-benzyl amino alcohol.

Example 56 N (phenoxyiscpropyl) N 2 thenylethanolamine:

N- (phenoxyisopropyl) -ethanolamine, an intermediate in the preparation of Example 1, is employed as a starting material. The secondary amino alcohol is heated with 2chloromethylthiophene in alcohol solution in the presence of sodium bicarbonate following the procedure used for reaction of N-(phenoxyisopropyl) -ethanolamine with benzyl chloride (see Example 1). The N- (phenoxyisopropyl)-N-thenylethanolamine may be heated with thionyl chloride in chloroform solution to obtain the fi-chlorethylamine hydrochloride, M. P. 118.5-'.5 C

Example 57 N (phenoxyisopropyl) N (5 chloro 2 thenyl) -ethanolamine:

This compound will be prepared by the same procedure as described for Example 56 with 5- chloro-Zchloromethylthiophene used in place of 2-chloromethylthiophene.

Example 58 N (phenoxyisopropyl) N (3 thionyl methyl) -ethanolamine:

NCH2CH2OH [CH2 In the procedure of Example 58, an equivalent amount of B-bromomethylthiophene will replace 2-choloromethylthiophene.

Example 59 N- (phenoxyisopropyl) -N- (2,4-dichlorobenzyl) ethanolamine A mixture of 24 g. of N-(phenoxyisopropyD- ethanolamine, prepared as described in Example 1, 24 g. of 2,4-dichlorobenzyl chloride, 10.3 g. of anhydrous sodium bicarbonate and 250 ml. of alcohol is stirred and refluxed for ten hours and then ml. of alcohol is removed by distillation. The concentrated reaction mixture is poured into water and the organic material extracted into ether. The ether solution is dried and distilled 27 to give N-(phenoxyisopropyl) -N-(2,4-dichloro benzyl) -ethanolamine, B. P. 1l9-121 C. at 2 mm. Using this amino alcohol as an intermediate, twenty grams thereof is dissolved in 100 ml. of dry chloroform. Anhydrous hydrogen chloride is introduced until the solution is acid and then 8.4 g. of thionyl chloride is added. After the solution is refluxed for two hours, the solvent is evaporated at reduced pressure and the crude product is recrystallized from alcohol and ether. The purified N- (phenoxyisopropyl) -N- (2,4-dichlorobenzyl) B chlorethylamine hydrochlororide melts at 116-118.5 0.

Example 60 N-(o-ethylphenoxyisopropyl) N benzylethanolamine:

l @OCHPCH-CH;

With o-ethylphenol as starting material, this compound is prepared by the process described in Example 4.

Example 61 N-(o propylphenoxyisopropyl) -N-benzylethanolamine:

CHz-CHr-CHr-CH:

By replacing the p-cresol of Example 4 by a H stoichiometrically equivalent amount of o-butylphenol and following generally the procedure of Example 4, there is obtained the above amino alcohol.

Example 63 N-(o-isobutylphenoxyisopropyl) N benzylethanolamine I @ocm-on-om The procedure of Example 4 will be followed using an equivalent amount of o-isobutylphenol in place of p-cresol.

28 Example 64 N-(o-methoxyphenoxyisopropyl) N benzylethyl-anolamine:

OCH:

The procedure of Example 4 is followed using guaiacol as the starting material in place of p-cresol. In the first step l-(o-methoxyphenoxy) -2-propanol is formed and this is converted, with thionyl chloride, into l-(o-methoxyphenoxy) -2-chloropropane. Reaction of the chloro compound with ethanolamine produces N (o-methoxyphenoxyisopropyl) ethanolamine, M. P. 56-57 C., which is benzylated by means of benzyl chloride. Using this amino alcohol as an intermediate, the hydroxy group is replaced by chlorine with thionyl chloride.

Example 65 N-(o benzylphenoxyisopropyl) -N-benzy1ethanolamine:

With o-benzylphenol as the starting material the procedure of Example 4 will be followed to produce the above compound.

In the foregoing examples alcohols according to this invention are exemplified. However, it will be understood and readily appreciated by those skilled in the art that the foregoing examples will illustrate the structure of organic or inorganic salts generally and will serve as specific examples of those organic and inorganic salts heretofore mentioned specifically by the writing in the several foregoing illustrative structures of the chemical symbols for the several acid groups heretofore specifically mentioned or of the acid group of any other desired organic or inorganic acid.

As will be apparent, the organic and inorganic salts contemplated by this invention will be prepared from the alcohols in a manner usual and well known to those skilled in the art, as by neutralizing the bases with organic or inorganic acids.

The compounds contemplated by this invention will be variously optically inactive or optically active and it will be understood that the optically inactive and optically active forms of the compounds contemplated by this invention are all included within the scope of this invention.

The various types of compounds having the structure embodying this invention as illustrated by the above specific examples and examples of the various types of compounds will be readily prepared by the general methods of preparation described above as exemplified by the description of the preparation of the several specific examples. The starting material for the preparation of any given compound within the structure contemplated by this invention will be found among known compounds, or, its structure being obvious with reference to any particular compound desired to be prepared, will be readily prepared by known methods.

This is a continuation-in-part of application, Serial No. 97,926, filed June 8, 1949, now abandoned.

What is claimed is:

1. A compound of the class consisting of a free base and its acid addition salts, the free base having the structure in which W and W are selected from the group consisting of hydrogen, alkyl containing not more than 4 carbon atoms, OH, CHsO, chlorine and bromine; Y is selected from the group consisting of oxygen and sulfur; Z is selected from the group consisting of benzyl, benzyl substituted in the phenyl nucleus by CH3, benzyl substituted in the phenyl nucleus by CI-IsO, benzyl substituted in the phenyl nucleus by C1, phenoxyalkyl the alkyl portion of which contains not more than 3 carbon atoms, phenoxyalkyl with the phenyl portion substituted by alkyl containing not more than 4 carbon atoms, phenoxyalkyl with the phenyl portion substituted by OH, phenoxyalkyl with the phenyl portion substituted by CHsO, phenoxyalkyl with the phenyl portion substituted by C1, the alkyl portion of all of said phenoxyalkyl groups containing not more than 3 carbon atoms, thenyl, thenyl substituted by chlorine, and thenyl substituted by bromine; and R is selected from the group consisting of hydrogen and CH3. 4o

2. The compound having the structure:

N-CHz-CHz-OH 3. The compound having the structure:

4. The compound having the structure:

@oom-on-om N-CHz-CHz-OH 5. The compound having the structure:

6. The compound having the structure:

Q0 CHr-OH-CH:

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Jour. of Pharm. and Ex. Therap., vol. 97, pp. 25-47 (September 1949). 

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS ACID ADDITION SALTS, THE FREE BASE HAVING THE STRUCTURE 